ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism

Granchi, Carlotta

doi:10.1016/j.ejmech.2018.09.001

Cited by 170 publications

(153 citation statements)

References 111 publications

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“…Two inhibitors of ELOVL6 were able to reduce the fatty acid composition of hepatocytes and the liver in a murine model of obesity [36,37], but the effects of these compounds on cancer cells have not been explored. Another potential druggable target to influence ELOVL6 expression is ATP citrate lyase (ACLY), which has a wide variety of inhibitors [38]. Expression of ELOVL6 has been shown to decrease concurrently with ACLY inhibition [39].…”

Section: Discussionmentioning

confidence: 99%

Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

Prusinkiewicz

Gameiro

Ghasemi

et al. 2020

Cancers

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Human papillomavirus (HPV) causes an increasing number of head and neck squamous cell carcinomas (HNSCCs). Altered metabolism contributes to patient prognosis, but the impact of HPV status on HNSCC metabolism remains relatively uncharacterized. We hypothesize that metabolism-related gene expression differences unique to HPV-positive HNSCC influences patient survival. The Cancer Genome Atlas RNA-seq data from primary HNSCC patient samples were categorized as 73 HPV-positive, 442 HPV-negative, and 43 normal-adjacent control tissues. We analyzed 229 metabolic genes and identified numerous differentially expressed genes between HPV-positive and negative HNSCC patients. HPV-positive carcinomas exhibited lower expression levels of genes involved in glycolysis and higher levels of genes involved in the tricarboxylic acid cycle, oxidative phosphorylation, and β-oxidation than the HPV-negative carcinomas. Importantly, reduced expression of the metabolism-related genes SDHC, COX7A1, COX16, COX17, ELOVL6, GOT2, and SLC16A2 were correlated with improved patient survival only in the HPV-positive group. This work suggests that specific transcriptional alterations in metabolic genes may serve as predictive biomarkers of patient outcome and identifies potential targets for novel therapeutic intervention in HPV-positive head and neck cancers.

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Section: Discussionmentioning

confidence: 99%

Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

Prusinkiewicz

Gameiro

Ghasemi

et al. 2020

Cancers

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“…S12 ). Taken together, our results demonstrate that imaging of citrate concentration dynamics with Citron1 and Citroff1 provides a sensitive method for the detection of ACLY activity that could potentially be used in cell-based screens for ACLY inhibitors 4 .…”

Section: Physiological and Pharmacological Alteration Of Subcellular mentioning

confidence: 60%

“…Huang et al have noted that citrate can have both anti-tumor and tumor-promoting effects, depending on its local concentration 2 . For example, despite the decreased reliance on the TCA cycle in tumor cells (the Warburg effect) 3 , some cell types appear to have an increased cytosolic pool of citrate that may serve as a source of acetyl-CoA to be used for increased fatty acid biosynthesis 4 . Conversely, other evidence suggests that a decrease in cytosolic citrate is associated with tumor aggressiveness, possibly due to increased resistance to apoptosis as a consequence of decreased acetyl-CoA dependent protein acetylation 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, other evidence suggests that a decrease in cytosolic citrate is associated with tumor aggressiveness, possibly due to increased resistance to apoptosis as a consequence of decreased acetyl-CoA dependent protein acetylation 5 . As these examples demonstrate, citrate is central to the dysregulated metabolism of cancer cells, and enzymes that produce (i.e., CS), transport (i.e., CiC), and metabolize (i.e., ACLY and ACO2), citrate have been proposed as potential targets for new therapeutic approaches to cancer 2,4 . Further investigation of the role of citrate in tumor development will require new methods that could be used for sensitive detection of citrate in subcellular compartments of cells in in vivo tumor models.…”

Section: Introductionmentioning

confidence: 99%

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High performance intensiometric direct- and inverse-response genetically encoded biosensors for citrate

Zhao

Shen

Wen

et al. 2020

Preprint

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Motivated by the growing recognition of citrate as a central metabolite in a variety of biological processes associated with healthy and diseased cellular states, we have developed a series of high-performance genetically encoded citrate biosensors suitable for imaging of citrate concentrations in mammalian cells. The design of these biosensors was guided by structural studies of the citrate-responsive sensor histidine kinase, and took advantage of the same conformational changes proposed to propagate from the binding domain to the catalytic domain. Following extensive engineering based on a combination of structure guided mutagenesis and directed evolution, we produced an inverse-response biosensor (ΔF/F min~1 8) designated Citroff1 and a direct-response biosensor (ΔF/F min~9 ) designated Citron1. We report the x-ray crystal structure of Citron1 and demonstrate the utility of both biosensors for qualitative and quantitative imaging of steady-state and pharmacologically-perturbed citrate concentrations in live cells.

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“…They also observed that the same treatments in mice reduced in vivo tumor growth. Thus, glucose metabolism is linked to lipid synthesis, an important feature of cancer metabolism, and the key enzyme that is involved in this biochemical pathway is ATP citrate lyase (Zaidi et al, 2012;Granchi, 2018).…”

Section: Atp Citrate Lyase Activity In Hbv Infected Liver Cellsmentioning

confidence: 99%

Role of Hepatitis B Virus Large Surface Protein in Promoting Activation of Nuclear SREBPs via ER Stress: Implications for Hepatocellular Carcinoma

Ghosh¹

2019

IJB

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One of the most common fatal malignancies in the world is Hepatocellular carcinoma (HCC) and hepatitis B virus (HBV) infection has been identified as a leading risk factor for HCC. Studies have suggested that during infection the large surface viral protein of HBV (LS protein) is targeted to the endoplasmic reticulum (ER) of the host liver cell, where its accumulation causes ER stress leading to HCC. The LS protein is also believed to stimulate the lipogenic activity of the ATP citrate lyase (ACL) enzyme, leading to excessive synthesis of lipids required for the rapidly dividing liver tumor cell. Here, I propose a hypothesis linking viral LS protein-induced ER stress to generation of the mature transcriptionally active nuclear form of sterol regulatory element-binding protein (nSREBP). nSREBP translocates to the nucleus and binds to sterol regulatory elements (SRE) present in the ATP citrate lyase (ACL) gene promoter, thereby elevating ACL transcription levels and overproduction of the ACL enzyme protein. Inhibition of LS protein activity in the ER may provide a therapeutic strategy in treating HBV induced HCC.

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ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism

Cited by 170 publications

References 111 publications

Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

High performance intensiometric direct- and inverse-response genetically encoded biosensors for citrate

Role of Hepatitis B Virus Large Surface Protein in Promoting Activation of Nuclear SREBPs via ER Stress: Implications for Hepatocellular Carcinoma

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